The G protein-coupled taste receptor T1R1/T1R3 regulates mTORC1 and autophagy

Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, 6001 Forest Park Road, Dallas, TX 75390-9041, USA.
Molecular cell (Impact Factor: 14.02). 09/2012; 47(6):851-62. DOI: 10.1016/j.molcel.2012.08.001
Source: PubMed


Cells continually assess their energy and nutrient state to maintain growth and survival and engage necessary homeostatic mechanisms. Cell-autonomous responses to the fed state require the surveillance of the availability of amino acids and other nutrients. The mammalian target of rapamycin complex 1 (mTORC1) integrates information on nutrient and amino acid availability to support protein synthesis and cell growth. We identify the G protein-coupled receptor (GPCR) T1R1/T1R3 as a direct sensor of the fed state and amino acid availability. Knocking down this receptor, which is found in most tissues, reduces the ability of amino acids to signal to mTORC1. Interfering with this receptor alters localization of mTORC1, downregulates expression of pathway inhibitors, upregulates key amino acid transporters, blocks translation initiation, and induces autophagy. These findings reveal a mechanism for communicating amino acid availability through a GPCR to mTORC1 in mammals.

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Available from: Ralph J Deberardinis, Sep 13, 2015
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    • "Human taste sensations are mainly categorized as: sweet, sour, salty, bitter, and umami. In addition to the tongue, taste receptors are also present in multiple peripheral organs including gut, pancreas and also the brain (2). Studies have shown that in the gut, the secretion of satiation peptides (GLP-1 and PYY) is regulated by the type 1 taste receptor T1R2/T1R3 heterodimers (3, 4), whereas in the pancreatic β-cells, the T1R1/T1R3 heterodimers regulate autophagy and insulin secretion (2, 5). "
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    ABSTRACT: Taste perception is controlled by taste cells that are present in the tongue and produce and secrete various metabolic hormones. Recent studies have demonstrated that taste receptors in tongue, gut and the pancreas are associated with local hormone secretion. The aim of this study was to determine whether there is a link between taste sensitivity and levels of circulating metabolic hormones in human and whether taste sensitivity is potentially related to peripheral metabolic regulation. 31 subjects were recruited and separated into tasters and non-tasters based on their phenol thiocarbamide (PTC) bitter taste test results. Fasting plasma and saliva were collected and levels of hormones and cytokines were assayed. We observed significant differences in both hormone levels and hormone-body mass index (BMI) correlation between tasters and non-tasters. Tasters had higher plasma levels of leptin (p=0.05), tumor necrosis factor-α (TNF-α) (p=0.04), and Insulin-like growth factor 1 (IGF-1) (p=0.03). There was also a trend towards increased IGF-1 levels in the saliva of tasters (p=0.06). We found a positive correlation between plasma levels of glucose and BMI (R=0.4999, p=0.04) exclusively in non-tasters, not in tasters. In contrast, plasma C-peptide levels were found to be positively correlated to BMI (R=0.5563, p=0.03) in tasters. Saliva TNF-α levels were negatively correlated with BMI in tasters (R= -0.5908, p=0.03). Our findings demonstrate that there are differences in circulating levels of leptin, TNF-α and IGF-1 between tasters and non-tasters. These findings indicate that in addition to regulate eating behaviours, taste perception could also affect energy metabolism by controlling hormone secretion. People with different taste sensitivity may respond differently to the nutrient stimulation. Further work investigating the link between taste perception and peripheral metabolic control could potentially lead to the development of novel therapies for obese control.
    Full-text · Article · Jul 2014 · Frontiers in Endocrinology
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    • "eceptor . But this is unlikely because this enzyme plays a central role in amino acid catabolism and its downregulation would have resulted in increased intracellular amino acid concentra - tions under these conditions , which was not observed . Another , plausible , possibility is that AMPK was activated . However , AMPK was inhibited , instead ( Wauson et al . 2012 ) . A third possibility , i . e . , that leucyl - tRNA synthetase was affected by T1R1 / T1R3 receptor knockdown , was not explored ."
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    ABSTRACT: Amino acids not only participate in intermediary metabolism but also stimulate insulin-mechanistic target of rapamycin (MTOR)-mediated signal transduction which controls the major metabolic pathways. Among these is the pathway of autophagy which takes care of the degradation of long-lived proteins and of the elimination of damaged or functionally redundant organelles. Proper functioning of this process is essential for cell survival. Dysregulation of autophagy has been implicated in the etiology of several pathologies. The history of the studies on the interrelationship between amino acids, MTOR signaling and autophagy is the subject of this review. The mechanisms responsible for the stimulation of MTOR-mediated signaling, and the inhibition of autophagy, by amino acids have been studied intensively in the past but are still not completely clarified. Recent developments in this field are discussed.
    Full-text · Article · Jun 2014 · Amino Acids
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    • "Interference with some of those signaling pathways can trigger autophagy. For example, reducing the expression of T1R1/TIR3, a broadly expressed GPCR dimer that senses amino acid availability, altered the location of mTORC1, upregulated key amino acid transporters, and induced autophagy in both HeLa and H9C2 cells [47]. But it is unlikely that T1R1/T1R3 signals via a Gi-linked signaling pathway, but rather a Gq- or Gq family member or gustducin. "
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    ABSTRACT: In macrophages autophagy assists antigen presentation, affects cytokine release, and promotes intracellular pathogen elimination. In some cells autophagy is modulated by a signaling pathway that employs Gαi3, Activator of G-protein Signaling-3 (AGS3/GPSM1), and Regulator of G-protein Signaling 19 (RGS19). As macrophages express each of these proteins, we tested their importance in regulating macrophage autophagy. We assessed LC3 processing and the formation of LC3 puncta in bone marrow derived macrophages prepared from wild type, Gnai3(-/-), Gpsm1(-/-), or Rgs19(-/-) mice following amino acid starvation or Nigericin treatment. In addition, we evaluated rapamycin-induced autophagic proteolysis rates by long-lived protein degradation assays and anti-autophagic action after rapamycin induction in wild type, Gnai3(-/-), and Gpsm1(-/-) macrophages. In similar assays we compared macrophages treated or not with pertussis toxin, an inhibitor of GPCR (G-protein couple receptor) triggered Gαi nucleotide exchange. Despite previous findings, the level of basal autophagy, autophagic induction, autophagic flux, autophagic degradation and the anti-autophagic action in macrophages that lacked Gαi3, AGS3, or RGS19; or had been treated with pertussis toxin, were similar to controls. These results indicate that while Gαi signaling may impact autophagy in some cell types it does not in macrophages.
    Full-text · Article · Nov 2013 · PLoS ONE
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